Method for the synthesis of compounds of formula I and their uses thereof

ABSTRACT

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer&#39;s disease, erectile dysfunction, and tumor invasion and metastasis.

[0001] This application claims the benefit, under 35 U.S.C. § 119, ofprovisional application U.S. Ser. No. 60/207,343, filed May 30, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to compounds which are modulators of thereceptor for advanced glycated end products (RAGE) and interaction withits ligands such as advanced glycated end products (AGEs),S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, for the management,treatment, control, or as an adjunct treatment of diseases caused byRAGE.

BACKGROUND OF THE INVENTION

[0003] Incubation of proteins or lipids with aldose sugars results innonenzymatic glycation and oxidation of amino groups on proteins to formAmadori adducts. Over time, the adducts undergo additionalrearrangements, dehydrations, and cross-linking with other proteins toform complexes known as Advanced Glycosylation End Products (AGEs).Factors which promote formation of AGEs included delayed proteinturnover (e.g. as in amyloidoses), accumulation of macromolecules havinghigh lysine content, and high blood glucose levels (e.g. as in diabetes)(Hori et al., J. Biol. Chem. 270: 25752-761, (1995)). AGEs haveimplicated in a variety of disorders including complications associatedwith diabetes and normal aging.

[0004] AGEs display specific and saturable binding to cell surfacereceptors on endothelial cells of the microvasculature, monocytes andmacrophages, smooth muscle cells, mesengial cells, and neurons. TheReceptor for Advanced Glycated Endproducts (RAGE) is a member of theimmunoglobulin super family of cell surface molecules. The extracellular(N-terminal) domain of RAGE includes three immunoglobulin-type regions,one V (variable) type domain followed by two C-type (constant) domains(Neeper et al., J. Biol. Chem. 267:14998-15004 (1992). A singletransmembrane spanning domain and a short, highly charged cytosolic tailfollow the extracellular domain. The N-terminal, extracellular domaincan be isolated by proteolysis of RAGE to generate soluble RAGE (sRAGE)comprised of the V and C domains.

[0005] RAGE is expressed in most tissues, and in particular, is found incortical neurons during embryogenesis (Hori et al., J. Biol. Chem.270:25752-761 (1995)). Increased levels of RAGE are also found in agingtissues (Schleicher et al., J. Clin. Invest. 99 (3): 457-468 (1997)),and the diabetic retina, vasculature and kidney (Schmidt et al., NatureMed. 1:1002-1004 (1995)). Activation of RAGE in different tissues andorgans leads to a number of pathophysiological consequences. RAGE hasbeen implicated in a variety of conditions including: acute and chronicinflammation (Hofmann et al, Cell 97:889-901 (1999)), the development ofdiabetic late complications such as increased vascular permeability(Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy(Teillet et al., J. Am. Soc. Nephrol. 11:1488-1497 (2000)),atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM,Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al.,Diabetologia 42:603-607 (1999)). RAGE has also been implicated inAlzheimer's disease (Yan et al., Nature 382: 685-691, (1996)), erectiledysfunction, and in tumor invasion and metastasis (Taguchi et al.,Nature 405: 354-357, (2000)).

[0006] In addition to AGEs, other compounds can bind to, and modulateRAGE. In normal development, RAGE interacts with amphoterin, apolypeptide which mediates neurite outgrowth in cultured embryonicneurons (Hori et al., 1995). RAGE has also been shown to interact withEN-RAGE, a protein having substantial similarity to calgranulin (Hofmannet al., Cell 97:889-901 (1999)). RAGE has also been shown to interactwith β-amyloid (Yan et al., Nature 389:589-595, (1997); Yan et al.,Nature 382:685-691 (1996); Yan et al., Proc. Natl.Acad. Sci.,94:5296-5301 (1997)).

[0007] Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE,β-amyloid, CML (N^(ε)-Carboxymethyl lysine), and amphoterin to RAGE hasbeen shown to modify expression of a variety of genes. For example, inmany cell types interaction between RAGE and its ligands generatesoxidative stress, which thereby results in activation of the freeradical sensitive transcription factor NF-KB, and the activation ofNF-κB regulated genes, such as the cytokines IL-1β, TNF-α, and the like.In addition, several other regulatory pathways, such as those involvingp21 ras, MAP kinases, ERK1 and ERK2, have been shown to be activated bybinding of AGEs and other ligands to RAGE. In fact, transcription ofRAGE itself is regulated at least in part by NF-KB. Thus, an ascending,and often detrimental, spiral is fueled by a positive feedback loopinitiated by ligand binding. Antagonizing binding of physiologicalligands to RAGE, therefore, is our target for down-regulation of thepathophysiological changes brought about by excessive concentrations ofAGEs and other ligands for RAGE.

[0008] Thus, there is a need for the development of compounds thatantagonize binding of physiological ligands to the RAGE receptor.

SUMMARY OF THE INVENTION

[0009] This invention provides compounds which are useful as RAGEmodulators. In a preferred embodiment, the present invention providescompounds of Formula (I) as depicted below, to methods of theirpreparation, pharmaceutical compositions comprising the compounds and totheir use in treating human or animal disorders. The compounds of theinvention are useful as modulators of the interaction of the receptorfor advanced glycated end products (RAGE) with its ligands such asadvanced glycated end products (AGEs), S100/calgranulin/EN-RAGE,β-amyloid and amphoterin, and thus are useful for the management,treatment, control, and/or as an adjunct treatment of diseases in humanscaused by RAGE. Such diseases or disease states include acute andchronic inflammation, the development of diabetic late complicationssuch as increased vascular permeability, nephropathy, atherosclerosis,and retinopathy, the development of Alzheimer's disease, erectiledysfunction, and tumor invasion and metastasis.

DETAILED DESCRIPTION OF THE INVENTION

[0010] In a first aspect, the present invention provides a compoundcomprising at least one moiety of the formula

[0011] wherein L₁ and L₂ are each a hydrocarbon group of from 1 to 6carbons or a direct bond, and Aryl₁ and Aryl₂ are aryl, wherein each ofAryl₁ and Aryl₂ are substituted by at least one lipophilic group. In apreferred embodiment, the lipophilic group is selected from C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylaryl, or C₁₋₆ alkoxyaryl. We have found suchcompounds to be useful in the modulation, preferably in the inhibitionof the interaction of RAGE with its physiological ligands, as will bediscussed in more detail below.

[0012] In a second aspect, the present invention provides compounds ofFormula (I):

[0013] wherein

[0014] R₁ and R₂ are independently selected from

[0015] a) —H;

[0016] b) —C₁₋₆ alkyl;

[0017] c) -aryl;

[0018] d) —C₁₋₆ alkylaryl;

[0019] e) —C(O)—O—C₁₋₆ alkyl;

[0020] f) —C(O)—O—C₁₋₆ alkylaryl;

[0021] g) —C(O)—NH—C₁₋₆ alkyl;

[0022] h) —C(O)—NH—C₁₋₆ alkylaryl;

[0023] i) —SO₂—C₁₋₆ alkyl;

[0024] j) —SO₂—C₁₋₆ alkylaryl;

[0025] k) —SO₂-aryl;

[0026] l) —SO₂—NH—C₁₋₆ alkyl;

[0027] m) —SO₂—NH—C₁₋₆ alkylaryl;

[0028] n)

[0029] o) —C(O)—C₁₋₆ alkyl; and

[0030] p) —C(O)—C₁₋₆ alkylaryl;

[0031] R₃ is selected from

[0032] a) —C₁₋₆ alkyl;

[0033] b) -aryl; and

[0034] c) —C₁₋₆ alkylaryl;

[0035] R₄ is selected from

[0036] a) —C₁₋₆ alkylaryl;

[0037] b) —C₁₋₆ alkoxyaryl; and

[0038] c) -aryl;

[0039] R₅ and R₆ are independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₁-C₆ alkylaryl, and aryl; and wherein the aryland/or alkyl group(s) in R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₈,R₁₉, and R₂₀ may be optionally substituted 1-4 times with a substituentgroup, wherein said substituent group(s) or the term substituted refersto groups selected from the group consisting of:

[0040] a) —H;

[0041] b) —Y—C₁₋₆ alkyl;

[0042] —Y-aryl;

[0043] —Y—C—₁₋₆ alkylaryl;

[0044] —Y—C₁₋₆-alkyl-NR₇R₈; and

[0045] —Y—C₁₋₆-alkyl-W—R₂₀;

[0046] wherein Y and W are, independently selected from the groupconsisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—,—NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

[0047] c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and

[0048] R₁₈ and R₁₉ are independently selected from the group consistingof aryl, C₁-C₆ alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆alkoxyaryl;

[0049] R₂₀ is selected from the group consisting of aryl, C₁-C₆ alkyl,and C₁-C₆ alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected fromthe group consisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; and wherein

[0050] R₇ and R₈ may be taken together to form a ring having the formula—(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇ and R₈are attached, and/or R₅ and R₆ may, independently, be taken together toform a ring having the formula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to thenitrogen atoms to which R₅ and R₆ are attached, wherein m and n are,independently, 1, 2, 3, or 4; X is selected from the group consisting of—CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,—NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

[0051] or a pharmaceutically acceptable salt, solvate or prodrugthereof.

[0052] In the compounds of Formula (I), the various functional groupsrepresented should be understood to have a point of attachment at thefunctional group having the hyphen. In other words, in the case of —C₁₋₆alkylaryl, it should be understood that the point of attachment is thealkyl group; an example would be benzyl. In the case of a group such as—C(O)—NH—C₁₋₆ alkylaryl, the point of attachment is the carbonyl carbon.

[0053] In a preferred embodiment of this aspect of the invention, thecompounds of Formula (I) include those wherein:

[0054] R₁ is hydrogen;

[0055] R₂ is selected from

[0056] a) —H;

[0057] b) —C₁₋₆ alkyl;

[0058] c) —C₁₋₆ alkylaryl;

[0059] d) —C(O)—O—C₁₋₆ alkyl;

[0060] e) —C(O)—NH—C₁₋₆ alkyl;

[0061] f) —C(O)—NH—C₁₋₆ alkylaryl;

[0062] g) —SO₂—C₁₋₆ alkyl;

[0063] h) —SO₂—C₁₋₆ alkylaryl;

[0064] i) —SO₂—NH—C₁₋₆ alkyl; and

[0065] j)

[0066] k) —C(O)—C₁₋₆ alkyl;

[0067] l) —C(O)—C₁₋₆ alkylaryl;

[0068] R₃ is selected from

[0069] a) —C₁₋₄ alkylaryl; and

[0070] R₄ is selected from

[0071] a) —C₁₋₆ alkylaryl; and

[0072] b) -aryl;

[0073] and wherein the aryl group in R₁, R₂, R₃ and R₄ is optionallysubstituted 1-4 times with a substituent group, wherein said substituentgroup(s) or the term substituted refers to groups selected from thegroup consisting of:

[0074] a) —H;

[0075] b) —Y—C₁₋₆ alkyl;

[0076] —Y-aryl;

[0077] —Y—C—₁₋₆ alkylaryl;

[0078] —Y—C₁₋₆-alkyl-NR₇R₈; and

[0079] —Y—C₁₋₆-W—R₂₀;

[0080] wherein Y and W are, independently selected from the groupconsisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—,—NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

[0081] and

[0082] c) halogen, hydroxyl, carbamoyl, and carboxyl;

[0083] R₁₈ and R₁₉ are selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl;

[0084] R₂₀ is selected from the group consisting of aryl, C₁-C₆ alkyl,or C₁-C₆ alkylaryl, and wherein

[0085] R₇ and R₈ are selected from the group consisting of hydrogen,aryl, C₁-C₆ alkyl, or C₁-C₆ alkylaryl; and wherein

[0086] R₇ and R₈ may be taken together to form a ring having the formula—(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇ and R₈are attached, and/or R₅ and R₆ may, independently, be taken together toform a ring having the formula —(CH₂)_(m)—X—(CH₂ _(n)— bonded to thenitrogen atoms to which R₅ and R₆ are attached, wherein m, n, and X areas defined above.

[0087] In a further preferred embodiment, the R₃ groups above includeC₁₋₃ alkylaryl, said aryl optionally substituted by substituted 1-4times with a substituent group, wherein said substituent group(s) or theterm substituted refers to groups selected from the group consisting of:

[0088] —Y—C₁₋₆ alkyl;

[0089] —Y-aryl;

[0090] —Y—C—₁₋₆ alkylaryl;

[0091] —Y—C₁₋₆-alkyl-NR₇R₈; and

[0092] —Y—C₁₋₆-alkyl-W—R₂₀;

[0093] wherein Y and W are, independently selected from the groupconsisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—,—NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

[0094] A further preferred embodiment is the embodiment referred toabove, wherein aryl is phenyl or napthyl, optionally substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaryl, or C₁₋₆ alkoxyaryl.

[0095] Also included within the scope of the invention are theindividual enantiomers of the compounds represented by Formula (I) aboveas well as any wholly or partially racemic mixtures thereof. The presentinvention also covers the individual enantiomers of the compoundsrepresented by formula above as mixtures with diastereoisomers thereofin which one or more stereocenters are inverted.

[0096] Compounds of the present invention which are preferred for theirhigh biological activity are listed by name below in Table 1. TABLE 1Ex- am- ple Chemical Name  1 (R)-3-(2-Naphthyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride  2(R)-3-(2-Naphthyl)-2-aminopropionic Acid 4-Methoxycarbonyl-2-butoxyaniline Amide Hydrochloride  3(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide  4(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride  5(R)-3 -(2-Naphthyl)-2-methylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride  6(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Methoxycarbonyl-2-hydroxyaniline Amide  7(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-tert-Butoxycarbonyl-2-tert-butoxyaniline Amide  8(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-isobutoxyaniline Amide  9(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-isobutoxyaniline Amide Dihydrochloride 10(R)-3-Phenyl-2-tert-butoxycarbonylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 11(R)-3-Phenyl-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 12(R)-3 -(2-Naphthyl)-2-guanidinylpropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 13(R)-3-(4-Benzyloxyphenyl)-2-isopropylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyanilifle Amide 14(R)-3-(4-Benzyloxyphenyl)-2-benzylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 15(R)-3-(4-Benzyloxyphenyl)-2-methanesulfonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 16(R)-3-(4-Benzyloxyphenyl)-2-phenylsulfonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 17(R)-3-(4-Benzyloxyphenyl)-2-ethylcarbamoylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 18(R)-3-(4-Benzyloxyphenyl)-2-tert-butylcarbamoylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 19(R)-3-(4-Benzyloxypheny1)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxy-2-diethylaminoethoxyaniline Amide 20(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxy-2-diethylaminoethoxyaniline Amide Trihydrochloride 21(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-(3-Diethylamino-1-propoxy)-2-(3-diethylamino-1- propoxy)aniline Amide22 (R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-(3- Diethylamino-1-propoxy)-2-(3 -diethylamino-1-propoxyaniline Amide Trihydrochloride 23(R)-3-(4-B enzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-(2-furylmethoxy)aniline Amide 24(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl)-2-(2-furylmethoxy)aniline AmideDihydrochloride 25 (R)-3-(2-Naphthyl)-2-acetylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 26(R)-3-(4-Benzyloxyphenyl)-2-acetylaminopropioflic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide

[0097] Accordingly, in a further embodiment of the invention, there isprovided the above compounds, or the free amine, free acid, solvate,prodrug, or pharmaceutically acceptable salt thereof.

[0098] As used herein, the term “alkyl” refers to a straight or branchedchain hydrocarbon having the number of specified carbon atoms. Examplesof “alkyl” as used herein include, but are not limited to, methyl,n-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

[0099] As used herein, the term “alkylene” refers to a straight orbranched chain divalent hydrocarbon radical having from one to tencarbon atoms, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, and the like.

[0100] As used herein, the term “aryl” refers to a five-toseven-membered aromatic ring, or to an optionally substituted benzenering system, optionally containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible substitutions. Such a ring may be fused to oneor more five-to seven-membered aromatic rings optionally containing oneor more nitrogen, oxygen, or sulfur heteroatoms. Preferred aryl groupsinclude phenyl, biphenyl, 2-naphthyl, 1-naphthyl, phenanthryl,1-anthracenyl, pyridyl, furyl, furanyl, thiophenyl, indolyl,isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl,benzothienyl, benzindoyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzoxazolyl, and thelike. In this regard, especially preferred aryl groups include phenyl,2-naphthyl, 1-naphthyl, biphenyl, and like ring systems optionallysubstituted by tert-butyloxy, benzyloxy, n-butyloxy, ispropyloxy, andphenoxy.

[0101] As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

[0102] As used herein, the term “substituted” refers to substitutionwith the named substituent or substituents, multiple degrees ofsubstitution being allowed unless otherwise stated.

[0103] As used herein, the chemical structure terms “contain” or“containing” refer to in-line substitutions at any position along theabove defined substituent at one or more of any of O, S, SO, SO₂, N, orN-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—, —CH₂—NH—CH₃and so forth.

[0104] As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

[0105] As used herein, the term “biohydrolyzable ester” is an ester of adrug substance (in this invention, a compound of formula (I)) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable ester is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl esters (e.g., C₁-C₄), loweracyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters.

[0106] As used herein, the term “biohydrolyzable amide” is an amide of adrug substance (in this invention, a compound of general formula (I))which either a) does not interfere with the biological activity of theparent substance but confers on that substance advantageous propertiesin vivo such as duration of action, onset of action, and the like, or b)is biologically inactive but is readily converted in vivo by the subjectto the biologically active principle. The advantage is that, forexample, the biohydrolyzable amide is orally absorbed from the gut andis transformed to (I) in plasma. Many examples of such are known in theart and include by way of example lower alkyl amides, α-amino acidamides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

[0107] As used herein, the term “prodrug” includes biohydrolyzableamides and biohydrolyzable esters and also encompasses a) compounds inwhich the biohydrolyzable functionality in such a prodrug is encompassedin the compound of formula (I): for example, the lactam formed by acarboxylic group in R₂ and an amine in R₄, and b) compounds which may beoxidized or reduced biologically at a given functional group to yielddrug substances of formula (I). Examples of these functional groupsinclude, but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like. The term “pharmacologically effective amount” shall mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, animal or human that is being sought bya researcher or clinician. This amount can be a therapeuticallyeffective amount.

[0108] Whenever the terms “alkyl” or “aryl” or either of their prefixroots appear in a name of a substituent (e.g. arylalkoxyaryloxy) theyshall be interpreted as including those limitations given above for“alkyl” and “aryl”. Alkyl substituents shall be recognized as beingfunctionally equivalent to those having one or more degrees ofunsaturation. Designated numbers of carbon atoms (e.g. C₁₋₆) shall referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger substituent in which the term “alkyl” appearsas its prefix root. Similarly, the term “C₂-C₈ alkenyl” and C₂-C₈alkynyl” refer to groups having from 2 to 8 carbon atoms and at leastone carbon-carbon double bond or carbon-carbon triple bond,respectively. The term “lower”, for example in relation to “lower alkyl”refers to a C₁₋₆ alkyl group.

[0109] As used herein, the term “oxo” shall refer to the substituent ═O.

[0110] As used herein, the term “halogen” or “halo” shall includeiodine, bromine, chlorine and fluorine.

[0111] As used herein, the term “mercapto” shall refer to thesubstituent —SH.

[0112] As used herein, the term “carboxy” shall refer to the substituent—COOH.

[0113] As used herein, the term “cyano” shall refer to the substituent—CN.

[0114] As used herein, the term “aminosulfonyl” shall refer to thesubstituent —SO₂NH₂.

[0115] As used herein, the term “carbamoyl” shall refer to thesubstituent —C(O)NH₂.

[0116] The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds ofFormula (I) along with methods for the preparation of compounds ofFormula (I).

[0117] A suitably protected alpha-amino acid (1), where PG is an amineprotecting group such as tert-butoxycarbonyl, is treated with an aminein the presence of a coupling reagent such as but not limited todiisopropyl carbodiimide (DIC) to form the amide (2). The α-amino groupin (2) is then deprotected, employing a strong acid such as hydrogenchloride for the case where PG is tert-butoxycarbonyl, to afford thefree amine (3) either as the free base or as a salt (Scheme 1). Asuitably protected alpha-amino acid (1), where PG is an amine protectinggroup such as tert-butoxycarbonyl, is treated with an amine in thepresence of a coupling reagent such as but not limited to diisopropylcarbodiimide (DIC) to form the amide (2). The α-amino group in (2) isthen deprotected, employing a strong acid such as hydrogen chloride forthe case where PG is tert-butoxycarbonyl, to afford the free amine (3)either as the free base or as a salt (Scheme 1).

[0118] To further derivatize the amino group of compound (3), the freeamino compound, or the suitable salt thereof may be treated with analdehyde or ketone R₁₂C(O)R₁₁ in the presence of a reducing agent suchas sodium cyanoborohydride or sodium triacetoxyborohydride to affordcompound (4), where R₁₂ and R₁₁ are defined such that R₂ in (4) conformsto the specifications for Formula (I). Alternately, the amine compound(3) may be treated with tertiary amine base such as DIEA and a molarequvalent amount (or slight excess) of an alkylating agent of generalstructure R₂—Z, where Z is a nucleofugal group such as bromine, to formthe secondary amine compound (4) (Scheme 2). Amine (3) may be treatedwith a tertiary amine base such as DIEA and 2 molar equivalents (orslight excess) of an alkylating agent of general structure R₂—Z, where Zis a nucleofugal group such as bromine, to form the amine compound (5).Alternately, the amine compound (3) may be treated with an electrondeficient olefinic compound such as but not limited to ethyl acrylate,to afford the adduct intermediate (6). Compound (6) may be manipulated,employing methods known in the art such as hydride reduction, intransforming such an adduct to compounds of general structure (4).

[0119] To further derivatize the amino group of compound (3), the freeamino compound, or the suitable salt thereof may be treated with asulfonyl chloride such as benzenesulfonyl chloride to form thesulfonamide (7) (Scheme 3), where R₁₄ is C₁₋₆ alkyl, C₁₋₆ alkylaryl, oraryl. Alternately, an amine R₁₅—NH₂ may be treated with sulfurylchloride and the intermediate then treated with (2) to afford thesulfonylurea (7) where R₁₄ is —NH—C₁₋₆ alkyl or —NH—C₁₋₆ alkylaryl.

[0120] To further derivatize the amino group of compound (3), the freeamino compound, or the suitable salt thereof may be treated with anisocyanate R₁₅NCO in the presence or absence of a tertiary amine basesuch as TEA to form the urea (8) (Scheme 4), where R₁₅ is —C₁₋₆ alkyl or—C₁₋₆ alkylaryl and Q is NH. Alternately, compound (3) may be treatedwith R₁₅O—C(O)Cl and a tertiary amine base such as TEA to affordcompound (8) where R₁₅ is —C₁₋₆ alkyl or —C₁₋₆ alkylaryl and Q is O.

[0121] Compound (9) may be treated with triphenyl phosphine, eitherdiisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD)and an alcohol R₁₆—OH to form the compound (10) (Scheme 5), afterremoval of the protecting group PG. R₁₆ is —C₁₋₆ alkyl, —C₁₋₆ alkylaryl,—C₁₋₆ alkyl-OSi(C₁₋₆ alkyl)₃, —C₁₋₆ alkyl-OSi(C₁₋₆ alkylaryl)₃, or —C₁₋₆alkyl-NR₈R₉ (provided that neither R₈ nor R₉ are hydrogen). PG may be,for example, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

[0122] Compound (3) or a suitable salt thereof may be treated with aacid anhydride (R₁₇—CO)₂O and a base such as TEA in the presence orabsence of pyridine or DMAP to afford compound (11) (Scheme 6). Thesubstituent R₁₇ may be chosen such that the group R₁₇—C(O)— is asspecified for R₂ in Formula (I). Alternately, compound (3) may betreated with the acid chloride R₁₇—COCl and an tertiary amine base suchas TEA in the presence or absence of pyridine or DMAP to afford compound(11). Alternately, compound (3) may be treated with the carboxylic acidR₁₇—CO₂H and a carbodiimide reagent (i.e., a “coupling reagent”) such asEDC, DIC, or DCC in the presence or absence of HOBt to provide compound(11).

[0123] Compound (3) or a suitable salt thereof may be treated (Scheme 7)with an activated amidine reagent such as N,N′-bis-BOC-1-guanylpyrazoleor 3,5-dimethylpyrazole-1-carboxamidine nitrate in the presence of atertiary organic base such as TEA to generate the guanidine compound.Guanidine substituent protecting groups may be removed. For example,where N,N′-bis-BOC-1-guanylpyrazole is employed, the BOC groups of theadduct may be removed with a strong acid such as hydrogen chloride toafford the free guanidine compound (12), where R₅ and R₆ are as definedfor Formula (I).

[0124] General Experimental

[0125] LC-MS data was obtained using gradient elution on a Waters 600controller equipped with a 2487 dual wavelength detector and a LeapTechnologies HTS PAL Autosampler using an YMC Combiscreen ODS-A 50×4.6mm column. A three minute gradient was run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5%acetonitrile, 0.05% TFA) to 100% B. The MS was a Micromass ZMDinstrument. All data was obtained in the positive mode unless otherwisenoted. ¹H NMR data was obtained on a Varian 300 MHz spectrometer.

[0126] Abbreviations used in the Examples are as follows:

[0127] APCI=atmospheric pressure chemical ionization

[0128] BOC=tert-butoxycarbonyl

[0129] BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphoniumhexafluorophosphate

[0130] d=day

[0131] DIAD=diisopropyl azodicarboxylate

[0132] DCC=dicyclohexylcarbodiimide

[0133] DCM=dichloromethane

[0134] DIEA=diisopropylethylamine

[0135] DMF=N,N-dimethylformamide

[0136] DMPU=1,3-dimethypropylene urea

[0137] DMSO=dimethylsulfoxide

[0138] EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride

[0139] EDTA=ethylenediamine tetraacetic acid

[0140] ELISA=enzyme-linked immunosorbent assay

[0141] ESI=electrospray ionization

[0142] ether=diethyl ether

[0143] EtOAc=ethyl acetate

[0144] FBS=fetal bovine serum

[0145] g=gram

[0146] h=hour

[0147] HBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

[0148] HMPA=hexamethylphosphoric triamide

[0149] HOBt=1-hydroxybenzotriazole

[0150] Hz=hertz

[0151] i.v.=intravenous

[0152] kD=kiloDalton

[0153] L=liter

[0154] LAH=lithium aluminum hydride

[0155] LDA=lithium diisopropylamide

[0156] LPS=lipopolysaccharide

[0157] M=molar

[0158] m/z=mass to charge ratio

[0159] mbar=millibar

[0160] MeOH=methanol

[0161] mg=milligram

[0162] min=minute

[0163] mL=milliliter

[0164] mM=millimolar

[0165] mmol=millimole

[0166] mol=mole

[0167] mp=melting point

[0168] MS=mass spectrometry

[0169] N=normal

[0170] NMM=N-methylmorpholine, 4-methylmorpholine

[0171] NMR=nuclear magnetic resonance spectroscopy

[0172] p.o.=per oral

[0173] PBS=phosphate buffered saline solution

[0174] PMA=phorbol myristate acetate

[0175] ppm=parts per million

[0176] psi=pounds per square inch

[0177] R_(f)=relative TLC mobility

[0178] rt=room temperature

[0179] s.c.=subcutaneous

[0180] SPA=scintillation proximity assay

[0181] TEA=triethylamine

[0182] TFA=trifluoroacetic acid

[0183] THF=tetrahydrofuran

[0184] THP=tetrahydropyranyl

[0185] TLC=thin layer chromatography

[0186] T_(r)=retention time

[0187] The following compounds are synthesized according to the Schemes.

EXAMPLE 1

[0188]

[0189] To a solution of BOC-2-naphthyl-(D)-alanine (3.15 g) in CH₂Cl₂(40 mL), HOBt (1.35 g) and DCC (2.2 g) were added at rt under nitrogenatmosphere. After 2 h NEt₃ (2.79 mL) and4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (3.8 g) wereadded followed by DMAP (122 mg). The reaction mixture is then stirred atrt for 3 d and filtered to remove dicyclohexylurea. The filtrate isconcentrated and purified by silica gel column chromatography to afford4.8 g of the amide Intermediate 1A. 1H NMR (CDCl3): 8.50 (d, 1H), 8.27(br s, 1H), 7.55-7.85 (m, 5H), 7.25-7.45 (m, 5H), 5.15 (br s, 1H), 4.60(br s, 1H), 4.38 (t, 2H), 3.6-3.9 (m, 2H), 3.30 (d, 2H), 2.82 (t, 2H),2.60 (q, 4H), 1.2-1.8 (m, 10H), 1.10 (t, 6H).

[0190] MS: m/z 606 (M+H)⁺

[0191] 120 mg of Intermediate 1A obtained above is stirred in 4 M HCl indioxane (2 mL) for 3 h. Solvent is then removed in vacuo and the residueobtained is treated with ether and stirred. The ether is decanted offand the ether wash is repeated twice more. The product is then driedunder vacuum to afford a pale yellow solid (90 mg), Example 1.

[0192] LC: T_(r) 1.53; MS: 506 (M+H)⁺

EXAMPLE 2

[0193]

[0194] Example 1 (115 mg) is dissolved in anhydrous methanol (5 mL) andtreated with 1M KOH in methanol (25 μL). The reaction mixture is stirredovernight at rt and added with 2 drops of acetic acid and stirred.Solvent is then removed in vacuo and the residue obtained is purified bysilica gel column chromatography to yield the methyl ester Intermediate2A (65 mg).

[0195] NMR (acetone-d6): 9.10 (br s, 1H), 8.42 (d, 2H), 7.20-7.80 (m,7H), 6.78 (br d, 1 h), 4.50 (br m, 1H), 4.0 (br m, 2H), 3.76 (s, 3H),3.20 (dd, 1H), 2.9-3.2 (m, 4H), 1.22 (q, 2H), 1.20 (s, 9H), 0.90 (t,3H).

[0196] MS: m/z 521 (M+H)⁺

[0197] Intermediate 2A is dissolved in 4M HCl in dioxane (2 mL) andstirred at rt for 3 h. Product is isolated as for Example 1 to affordExample 2 as a fluffy white solid (50 mg).

[0198] MS: m/z 421 (M+H)⁺

EXAMPLE 3

[0199]

[0200] To a solution of BOC-D-Tyr(Bzl)-OH (1.11 g) in CH₂Cl₂ (15 mL),HOBT (406 mg) and DCC (681 mg) were added at rt. After 2 h TEA (840 μL)and 4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (1.04 g)were added followed by DMAP (36 mg). The reaction mixture is thenstirred at rt for 3 d and filtered to remove dicyclohexylurea. Thefiltrate is concentrated and purified on a silica gel columnchromatography to afford 1.2 g of Example 3.

[0201] LC: T_(r) 2.18; MS: m/z 662 (M+H)⁺

EXAMPLE 4

[0202]

[0203] 165 mg of Example 3 is stirred in 4M HCl in dioxane (2 mL) for 3h. Product is isolated as for Example 1 to afford Example 4 as a paleyellow solid (105 mg).

[0204] LC: T_(r) 1.75; MS: m/z 562(M+H)⁺

EXAMPLE 5

[0205]

[0206] BOC-(2-naphthyl)-D-alanine (946 mg) is dissolved in anhydrous THFat rt, added with methyl iodide (1.5 mL) and cooled to 0° C. Solid NaH(400 mg; 60% dispersion in oil) is slowly added to it and the reactionis allowed to proceed overnight with gradual warming up to rt. After 24h the reaction mixture is diluted with a mixture of EtOAc and cold waterand stirred. The contents were then shaken a separatory funnel and thelayers were separated. The aqueous layer is then extracted with EtOAc.The organic extracts were combined, ished with water and brine and driedover anhydrous sodium sulfate. Solvent is removed in vacuo and theresidue obtained is purified by silica gel solumn chromatography toafford the acid Intermediate 5A (630 mg).

[0207] MS: m/z 230 (M+H)⁺

[0208] To a solution of Intermediate 5A obtained as above (616 mg) inCH₂Cl₂ (10 mL), HOBt (303 mg) and DCC (463 mg) were added at rt undernitrogen atmosphere. After 2 h triethylamine (651 μL) and4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (645 mg) wereadded followed by DMAP (36 mg). The reaction mixture is then stirred atrt for 4 d and filtered to remove dicyclohexylurea. The filtrate isconcentrated and purified on a silica gel column chromatography toafford Intermediate 5B (220 mg).

[0209] LC: T_(r) 2.45 min; MS: m/z 620 (M+H)⁺

[0210] Intermediate SB is then dissolved in 4M HCl in dioxane (4 mL) for3 h. Product is isolated as for Example 1 to afford Example 5 (160 mg).

[0211] MS: m/z 520 (M+H)⁺

EXAMPLE 6

[0212]

[0213] BOC-D-Tyr(Bzl)-OH (4.46 g, 12.0 mmol) is suspended in 50 mL ofDCM and to this is added DCC (2.72 g, 13.20 mmol) and HOBt (1.62 g,12.01 mmol) and the mixture stirred under nitrogen for 2 h.Triethylamine (3.3 mL) is added followed by 4-amino-3-hydroxy benzoicacid methyl ester (2.67 g, 13.20 mmol). The mixture is stirred for 4 d.The reaction mixture is filtered and the solid residue washed with DCM.The filtrate is then washed with 5% Na₂CO₃ solution (2×50 mL) followedby brine solution. The organic extract is dried over Na₂SO₄, filteredand concentrated and purified by flash chromatography on silica geleluted with EtOAc/hexanes (50:50) to obtain Example 6 as a solid (5.0g).

[0214] MS: m/z 521 (M+H)⁺

EXAMPLE 7

[0215]

[0216] The compound of Example 6 is saponified to afford the carboxylicacid by the general method employed in preparation of Intermediate 2A,to afford Intermediate 7A.

[0217] Intermediate 7A (0.050 g, 0.099 mM) in 3 mL of DCM is added 2drops each of BF₃Et₂O and H₃PO₄. The solution is then transferred to−78° C. and isobutylene gas bubbled through for 3 min and then allowedto warm to rt and stirred for 12 h. The solution is extracted withsaturated NaHCO₃ (2×10 mL), dried over Na₂SO₄ and concentrated to an oilwhich is purified on silica gel eluted with EtOAc/hexanes (30:70) toobtain Example 7 as a white solid (0.055 g).

[0218] MS: m/z 619 (M+H)⁺

EXAMPLE 8

[0219]

[0220] To Example 6 (0.05 g, 0.096 mmol) in 1 mL of THF is added 6 μL ofisobutyl alcohol and triphenylphosphine (0.025 g, 0.096 mmol) followedby dropwise addition of diisopropyl azodicarboxylate (0.019 g, 0.096mmol) at 0° C. The reaction is allowed to warm to rt and stirred for 18h. The solvent is removed under reduced pressure and the oil obtainedpurified by flash chromatography on silica gel eluting with EtOAc/hexane(30:70) to yield Intermediate 8A as an oil (43.6 mg, 79%). Intermediate8A is hydrolyzed to with 1M KOH solution in dioxane at 80° C. to providethe acid Intermediate 8B (0.015 g).

[0221] Intermediate 8B (0.015 g, 0.026 mmol) is dissolved in 1 mL of DCMand HBTU (0.020 g, 0.054 mmol) added. The mixture is stirred for 1 h and100 μL of TEA is added followed by N,N-diethylethanolamine (0.021 g,0.180 mmol). The resulting solution is stirred for 18 h. Afterconcentrating under reduced pressure, the crude product is purified onsilica gel eluted with EtOAc/hexane (50/50) to provide Example 8 as asolid (0.014 g).

[0222] LC: T_(r) 2.20 min; MS:m/z 662 (M+H)⁺

EXAMPLE 9

[0223]

[0224] Example 8 (7 mg) is treated with 4N HCl/dioxane as described orIntermediate 1A. The product (5 mg) is isolated as for Example 1 toafford Example 9.

[0225] MS: m/z 552 (M+H)⁺

EXAMPLE 10

[0226]

[0227] To a solution of BOC -D-phenylalanine (1.33 g) in DCM (15 mL),HOBT (743 mg) and DCC (1.24 g) were added at rt. After 2 h TEA (1.2 mL)and 4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (1.73 g)were added followed by DMAP (60 mg). The reaction mixture is thenstirred at rt for 3 d and filtered to remove dicyclohexylurea. Thefiltrate is concentrated and purified on a silica gel columnchromatography to afford 1.9 g of Example 10.

[0228] LC: T_(r) 2.05 min; MS: m/z 556 (M+H)⁺

EXAMPLE 11

[0229]

[0230] Example 10 (47 mg) is stirred in 4M HCl in dioxane (2 mL) for 3h. Product is isolated as for Example 1 to afford Example 11 as a paleyellow solid (38 mg).

[0231] C: T_(r) 0.83 min; MS: m/z 456 (M+H)⁺

EXAMPLE 12

[0232]

[0233] Example 1 (80 mg) is dissolved in anhydrous acetonitrile (3 mL)and treated with DIEA (60 μL) and N,N′-bis-BOC-1-guanylpyrazole (60 mg).The resulting mixture is then refluxed overnight. The reaction mixtureis then cooled to rt and diluted with EtOAc (5 mL). The mixture iswashed with water and brine and dried over anhydrous sodium sulfate.Solvent is removed in vacuo and the residue obtained is purified bysilica gel column chromatography to afford the BOC-protected guanadinoproduct Intermediate 12A (12 mg).

[0234] NMR: (acetone-d6) 8.8 (br s, 1H), 8.20 (d, 1H), 7.2-7.8 (m, 9H),4.95 (dd, 1H), 4.2 (br s, 2H), 3.65-3.85 (m, 4H), 3.0-3.3 (m, 4H), 1.25(s, 9H), 1.20 (m, 4H), 1.15 (s, 9H), 0.95 (3, 3H)

[0235] MS: m/z 748 (M+H)⁺

[0236] Intermediate 12A (12 mg) is treated with 4M HC/dioxane (0.5 mL)to remove the BOC group as described for Intermediate 1A, affordingExample 12 (4 mg).

[0237] MS: m/z 549 (M+H)⁺

EXAMPLE 13

[0238]

[0239] 53 mg (0.084 mmole) of Example 4 is dissolved in 5 mL methanol.To this is added 10 μL of acetone. After 40 min, 0.10 mL of 1 M sodiumcyanoborohydride in THF is added. The reaction is stirred overnight, thesolvent removed in vacuo, and the crude compound purified by flashchromatography on silica gel (4:1 hexane: EtOAc, 10% TEA) to yield 22 mgof Example 14.

[0240] LC: T_(r) 1.77 min; MS: m/z 603 (M+H)⁺

EXAMPLE 14

[0241]

[0242] 106 mg (0.168 mmol) of Example 4 is dissolved in 5 mL methanol.To this is added 60 μL of benzaldehyde, with stirring. After 12 h, 0.50mL of 1 M sodium cyanoborohydride in THF is added. The reaction isstirred overnight, the solvent removed in vacuo, and the crude compoundpurified by flash chromatography on silica gel (4:1 hexane: EtOAc, 10%TEA) to yield 48.3 mg of Example 14.

[0243] LC: T_(r) 1.83 min; MS: m/z 653 (M+H)⁺

EXAMPLE 15

[0244]

[0245] 12 mg (0.019 mmole) of Example 4 is suspended in 3.5 mL dry DCM.To this is added 10 μL of methanesulfonyl chloride (0.13 mmole). Thereaction is stirred overnight, then an additional 10 μL ofmethanesulfonyl chloride is added and the reaction allowed to stir foran additional 24 h. The solvent is removed in vacuo to yield 12.2 mg ofExample 15.

[0246] LC: T_(r) 1.99 min; MS: m/z 640 (M+H)⁺

EXAMPLE 16

[0247]

[0248] 15 mg (0.024 mmole) of Example 4 is suspended in 4.0 mL dry DCM.To this is added 10 μL (0.078 mmole) of benzenesulfonyl chloride. Thereaction is stirred overnight, then an additional 10 μL ofbenzenesulfonyl chloride is added and the reaction allowed to stir foran additional 24 h. The solvent is removed in vacuo to yield 16.8 mg ofExample 16.

[0249] LC: T_(r) 2.05 min; MS: m/z 702 (M+H)⁺

EXAMPLE 17

[0250]

[0251] 25 mg (0.040 mmole) of Example 4 is suspended in 5 mL dry DCM. Tothis is added 50 μL of ethyl isocyanate (0.63 mmole). The reaction isstirred overnight, and the solvent is removed in vacuo to yield 25.2 mgof Example 17.

[0252] LC: T_(r) 1.99 min; MS: m/z 633 (M+H)⁺

EXAMPLE 18

[0253]

[0254] 20 mg (0.032 mmole) of Example 4 is suspended in 5 mL dry DCM. Tothis is added 50 μL of tert-butyl isocyanate (0.44 mmole, 13.7 eq.). Thereaction is stirred overnight, then an additional 50 μL of tert-butylisocyanate is added and the reaction allowed to stir for an additional24 h. The solvent is removed in vacuo to yield 21.1 mg of Example 18.

[0255] LC: T_(r) 1.97 min; MS: m/z 661 (M+H)⁺

EXAMPLE 19

[0256]

[0257] To a solution of BOC-D-Tyr(Bzl)-OH (279 mg) and 4-aminoresorcinolhydrochloride (135 mg) in acetonitrile (2 mL) at rt, HBTU (285 mg) andpyridine (145 μL) were added in succession. The resulting mixture isstirred overnight. The deep reddish reaction mixture is diluted withEtOAc/water (5 mL/3 mL) and the layers were separated. The aqueous layeris further extracted with EtOAC (5 mL). The organic layers were combinedand washed with water and brine and dried over Na₂SO₄. The solution isfiltered and the solvent is removed in vacuo. The resulting crudeproduct is purified by silica gel column chromatography usingmethanol/CHCl₃/hexane (1:20:20) as eluent to afford 300 mg of the amideIntermediate 19A.

[0258] LC:T_(r) 2.17 min; MS:m/z 479 (M+H)⁺

[0259] 120 mg of Intermediate 19A is dissolved in THF (2 mL) at rt andadded with triphenyl phosphine (197 mg), and N,N-diethylaminoethanol(100 μL). The resulting solution is cooled to 0° C. and treated withdiisopropyl azodicarboxylate (DIAD) (152 mg). The reaction is allowed toproceed overnight with gradual warming up to rt. The reaction mixture isdiluted with EtOAc/water (5 mL/3 mL) and the layers were separated. Theaqueous layer is further extracted with EtOAc (5 mL). The organic layerswere combined and washed with water and brine and dried over Na₂SO₄. Thesolution is filtered and the solvent is removed in vacuo. The resultingcrude product is purified by silica gel column chromatography usingNEt₃/methanol/CHCl₃/hexane (1:2:40:40) as eluent to afford 100 mg ofExample 19.

[0260] LC: T_(r) 1.80 min; MS: m/z 677 (M+H)⁺

EXAMPLE 20

[0261]

[0262] 50 mg of Example 19 is stirred in 4M HCl in dioxane (1 mL) for 3h. Product is isolated as for Example 1 to afford Example 21 as a paleyellow solid (35 mg).

[0263] MS: m/z 576 (M+H)⁺

EXAMPLE 21

[0264]

[0265] 120 mg of Example 19 is dissolved in THF (2 mL) at rt and addedwith triphenyl phosphine (197 mg), and N,N-diethylaminopropanol (115μL). The resulting solution is cooled to 0° C. and added withdiisopropyl azodicarboxylate (DIAD) (152 mg). The reaction is allowed toproceed overnight with gradual warming up to rt. The reaction mixture isdiluted with EtOAc/water (5 mL/3 mL) and the layers were separated. Theaqueous layer is further extracted with EtOAc (5 mL). The organic layerswere combined and washed with water and brine and dried over Na₂SO₄. Thesolution is filtered and the solvent is removed in vacuo. The resultingcrude product is purified by silica gel column chromatography usingtriethylamine/methanol/CHCl₃/hexane (1:2:40:40) as eluent to afford 50mg of Example 21.

[0266] LC: T_(r) 1.84 min; MS: m/z 705 (M+H)⁺

EXAMPLE 22

[0267]

[0268] 30 mg of Example 21 is stirred in 4M HCl in dioxane (1 mL) for 3h. Product is isolated as for Example 1 to afford Example 22 as a paleyellow solid (20 mg).

[0269] MS: m/z 604 (M+H)⁺

EXAMPLE 23

[0270]

[0271] To example 6 (0.05 g, 0.096 mmol) in 1 mL of THF is added 6 uL offurfuryl alcohol and triphenylphosphine (0.025 g, 0.096 mmol) followedby dropwise addition of diisopropyl azodicarboxylate (0.019 g, 0.096mmol) at 00 C. The reaction is allowed to warm to rt and stirred for 18h. The solvent is removed under reduced pressure and the oil obtainedpurified by flash chromatography on silica gel eluting with EtOAc/hexane(30:70) to yield the aryl ether Intermediate 23A as an oil (43.0 mg).Intermediate 23A is hydrolyzed to the carboxylic acid using 1M KOHsolution in dioxane at 80° C. The acid obtained (0.02 g, 0.036 mmmol) isdissolved in 1 mL of DCM and HBTU (0.015 g, 0.039 mmol) added. Themixture is stirred for 1 h and 36 uL of TEA is added followed byN,N-diethylethanolamine (0.015 g, 0.130 mmol). The resulting solution isstirred for 18 h. After concentrating under reduced pressure, the crudeproduct is purified on silica gel eluting with EtOAc/hexane (1: 1) toobtain Example 23 as a solid (0.015 g).

[0272] MS: m/z 686 (M+H)⁺

EXAMPLE 24

[0273]

[0274] Example 23 (7 mg) is treated with 4N HCl/dioxane as described forIntermediate 1A, and the product is isolated as for Example 1 to obtainExample 24 (4 mg).

[0275] LC: T_(r) 1.87 min; MS: m/z 586 (M+H)⁺

EXAMPLE 25

[0276]

[0277] 20 mg of Example 1 is dissolved in pyridine (100 μL) and treatedwith acetic anhydride (100 μL) at rt and stirred for 1 h. The reactionmixture is added with ice/water mixture and extracted with EtOAc. Theorganic layers were combined and washed with 5% aqueous CuSO₄, water andbrine and dried over Na₂SO₄. The solution is filtered and the solvent isremoved in vacuo to provide Example 25 as a pale white solid (15 mg).

[0278] LC: T_(r) 1.90 min; MS:m/z 548 (M+H)⁺

EXAMPLE 26

[0279]

[0280] 30 mg of Example 4 is dissolved in pyridine (200 μL) and treatedwith acetic anhydride (150 μL) at rt and stirred for 1 h. The reactionmixture is treated with ice/water mixture and extracted with EtOAC. Theorganic layers were combined and washed with 5% aqueous CuSO₄, water andbrine and dried over Na₂SO₄. The solvent is removed in vacuo to provideExample 26 as a pale white solid (25 mg).

[0281] LC: T_(r) 1.97 min; MS: m/z 604 (M+H)⁺

[0282] In the above schemes, “PG” represents an amino protecting group.The term “amino protecting group” as used herein refers to substituentsof the amino group commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include the formyl group, thetrityl group, the phthalimido group, the trichloroacetyl group, thechloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blockinggroups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (“BOC”),2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; thebenzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, thediphenylphosphine oxide group and like amino-protecting groups. Thespecies of amino-protecting group employed is not critical so long asthe derivatized amino group is stable to the condition of subsequentreaction(s) on other positions of the compound of Formula (I) and can beremoved at the desired point without disrupting the remainder of themolecule. Preferred amino-protecting groups are the allyloxycarbonyl,the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl groups.Similar amino-protecting groups used in the cephalosporin, penicillinand peptide art are also embraced by the above terms. Further examplesof groups referred to by the above terms are described by J. W. Barton,“Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., PlenumPress, New York, N.Y., 1973, Chapter 2, and T. W. Greene, “ProtectiveGroups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981,Chapter 7. The related term “protected amino” defines an amino groupsubstituted with an amino-protecting group discussed above.

[0283] In Scheme 1, other methods of coupling or acylating the protectedamino acid to the compound of formula R⁴NH₂ can be utilized, for exampleDCC/HBT, HBTU, and BOP and other methods, including but not limited tothose listed in: Fernando Albericio and Louis A. Carpino “CouplingReagents and Activation” in Methods in Enzymology vol.289 (Gregg B.Fields ed), pplO4-126, Academic Press, San Diego, 1997.

[0284] I. Biological Assay

[0285] The following assay method is utilized to identify compounds ofFormula (I) which are effective in binding with RAGE, and hence usefulas modulators, preferably antagonists of RAGE. This method is alsodescribed and claimed in co-pending U.S. Ser. No. ______ (AttorneyDocket No. TTP2000-02) filed on this date.

General Assay Procedure

[0286] S100b, β-amyloid and CML (500 ng/100 μL/well) in 100 mM sodiumbicarbonate/sodium carbonate buffer (pH 9.8) is loaded onto the wells ofa NUNC Maxisorp flat bottom 96-well microtitre plate. The plate isincubated at 4° C. overnight. The wells are aspirated and treated with50 mM imidazole buffer saline (pH 7.2) (with 1 mM CaCl₂/MgCl₂)containing 1% bovine serum albumin (BSA) (300 μL/well) for two h at 37°C. The wells are aspirated and washed 3 times (400 μL/well) with 155 mMNaCl pH 7.2 buffer saline and soaked 10 seconds between each wash.

[0287] Test compounds are dissolved in nanopure water (concentration:10-100 μM). DMSO may be used as co-solvent. 25 μL of test compoundsolution in 2% DMSO is added, along with 75 μL sRAGE (4.0×10⁻⁴ mg/mLFAC) to each well and samples are incubated for 1 h at 37° C. The wellsare washed 3 times with 155 mM NaCl pH 7.2 buffer saline and are soaked10 seconds between each wash. Non-radioactive binding is performed byadding:

[0288] 10 μL Biotinylated goat F(ab′)2 Anti-mouse IgG. (8.0×10⁻⁴ mg/mL,FAC)

[0289] 10 μL Alk-phos-Sterptavidin (3×10⁻³ mg/mL FAC)

[0290] 10 μL Polyclonal antibody for sRAGE (FAC_(6.0×10) ⁻³ mg/mL) to 5mL 50 mM imidazole buffer saline (pH 7.2) containing 0.2% bovine serumalbumin and 1 mM CaCl₂. The mixture is incubated for 30 minutes at 37°C. 100 μL complex is added to each well and incubation is allowed toproceed at rt for 1 h. Wells are washed 3 times with wash buffer andsoaked 10 s between each wash. 100 μL 1 mg/mL (PNPP) in 1 Mdiethanolamine (pH adjusted to 9.8 with HCl) is added. Color is allowedto develop in the dark for 1 to 2 h at rt. The reaction is quenched with10 μL of stop solution (0.5 N NaOH in 50% ethanol) and the absorbance ismeasured spectrophotometrically with a microplate reader at 405 nm.

[0291] The following compounds of Formula I were synthesized accordingto the Schemes and tested according to the assay method described above.

[0292] IC₅₀ (μM) of ELISA assay represents the concentration of compoundat which 50% signal has been inhibited.

[0293] Compound inhibition of S-100b/RAGE interaction in Glioma cells byExample 1 had an IC50 of 3.3 μM. Thus, the cell based assay demonstratedeffective correlation with the binding of ELISA IC₅₀ value (1.75 μM).Functional Assay IC₅₀ (μM) Inhibition of NF-κB Example No. in GliomaCells ELISA Assay (5-100b) 1 3.3 1.75

[0294] ELISA Assay IC₅₀ (μM) Carboxymethyl Lysine Example No. S-100bAmyloid-β (CML)  1 1.75 3.4 2.29  2 5.1  — 3.16  3 1.32 1.5 1.5   4 0.822.2 1.12  5 2.88  1.81 1.27  6 6.3  NA NA  7 1-3 — 8    8 2.0  NA NA  91.6  NA NA 10 0.95 NA NA 11 10-30 NA NA 12 0.3-1.0 5   0.7  13 1   1  0.7  14 2.8  NA NA 15 10-30 NA NA 16 20-30 NA NA 17 10    NA NA 18 2.3 2   0.84 19 1.14  0.80 0.80 20 0.84 1   1   21 0.64  1.23 0.46 22 0.92 1.73 0.68 23 15.5  NA NA 24 2.7  NA NA 25 15    NA NA 26 5.6  NA NA

[0295] The invention further provides pharmaceutical compositionscomprising the RAGE modulating compounds of the invention. The term“pharmaceutical composition” is used herein to denote a composition thatmay be administered to a mammalian host, e.g., orally, topically,parenterally, by inhalation spray, or rectally, in unit dosageformulations containing conventional non-toxic carriers, diluents,adjuvants, vehicles and the like. The term “parenteral” as used herein,includes subcutaneous injections, intravenous, intramuscular,intracisternal injection, or by infusion techniques.

[0296] The pharmaceutical compositions containing a compound of theinvention may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous, or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany known method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, incorporated herein by reference, to formosmotic therapeutic tablets for controlled release.

[0297] Formulations for oral use may also be presented as hard gelatincapsules where the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, ora soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin, orolive oil.

[0298] Aqueous suspensions may contain the active compounds in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

[0299] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as a liquidparaffin. The oily suspensions may contain a thickening agent, forexample beeswax, hard paraffin or cetyl alchol. Sweetening agents suchas those set forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0300] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the active compoundin admixture with a dispersing or wetting agent, suspending agent andone or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

[0301] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample a liquid paraffm, or a mixture thereof. Suitable emulsifyingagents may be naturally-occurring gums, for example gum acacia or gumtragacanth, naturally-occurring phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example sorbitan monooleate, and condensationproducts of said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0302] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectible aqueous or oleaginous suspension. Thissuspension may be formulated according to the known methods usingsuitable dispersing or wetting agents and suspending agents describedabove. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conveniently employed as solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed usingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

[0303] The compositions may also be in the form of suppositories forrectal administration of the compounds of the invention. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will thus melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols, for example.

[0304] For topical use, creams, ointments, jellies, solutions ofsuspensions, etc., containing the compounds of the invention arecontemplated. For the purpose of this application, topical applicationsshall include mouth washes and gargles. The compounds of the presentinvention may also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes may be formed from a variety ofphospholipids, such as cholesterol, stearylamine, orphosphatidylcholines. Also provided by the present invention areprodrugs of the invention.

[0305] Pharmaceutically-acceptable salts of the compounds of the presentinvention, where a basic or acidic group is present in the structure,are also included within the scope of the invention. The term“pharmaceutically acceptable salts” refers to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid or by reacting theacid with a suitable organic or inorganic base. Representative saltsinclude the following salts: Acetate, Benzenesulfonate, Benzoate,Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate,Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride,Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate,Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate,Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide,Trimethylammonium and Valerate. When an acidic substituent is present,such as —COOH, there can be formed the ammonium, morpholinium, sodium,potassium, barium, calcium salt, and the like, for use as the dosageform. When a basic group is present, such as amino or a basic heteroarylradical, such as pyridyl, an acidic salt, such as hydrochloride,hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate,acetate, oxlate, maleate, pyruvate, malonate, succinate, citrate,tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate,ethanesulfonate, picrate and the like, and include acids related to thepharmaceutically-acceptable salts listed in the Journal ofPharmaceutical Science, 66, 2 (1977) p. 1-19.

[0306] Other salts which are not pharmaceutically acceptable may beuseful in the preparation of compounds of the invention and these form afurther aspect of the invention.

[0307] In addition, some of the compounds of the present invention mayform solvates with water or common organic solvents. Such solvates arealso encompassed within the scope of the invention.

[0308] Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, or prodrug therof, and one ormore pharmaceutically acceptable carriers, excipients, or diluents.

[0309] The compounds of the present invention selectively act asmodulators of RAGE binding to a single endogenous ligand, i.e.,selective modulators of β-amyloid-RAGE interaction, and therefore areespecially advantageous in treatment of Alzheimer's disease and relateddementias.

[0310] Further, the compounds of the present invention act as modulatorsof RAGE interaction with two or more endogenous ligands in preference toothers. Such compounds are advantageous in treatment of related orunrelated pathologies mediated by RAGE, i.e., Alzheimer's disease andcancer.

[0311] Further, the compounds of the present invention act as modulatorsof RAGE binding to each and every one of its ligands, thereby preventingthe generation of oxidative stress and activation of NF-KB regulatedgenes, such as the cytokines IL-1, and TNF-α. Thus, antagonizing thebinding of physiological ligands to RAGE prevent targetedpathophysiological consequences and useful for management or treatmentof diseases, i.e., AGE-RAGE interaction leading to diabeticcomplications, S100/EN-RAGE/calgranulin-RAGE interaction leading toinflammatory diseases, β-amyloid-RAGE interaction leading to Alzheimer'sDisease, and amphoterin-RAGE interaction leading to cancer.

I. RAGE and the Complications of Diabetes

[0312] As noted above, the compounds of the present invention are usefulin the treatment of the complications of diabetes. It has been shownthat nonenzymatic glycoxidation of macromolecules ultimately resultingin the formation of advanced glycation endproducts (AGEs) is enhanced atsites of inflammation, in renal failure, in the presence ofhyperglycemia and other conditions associated with systemic or localoxidant stress (Dyer, D., et al., J. Clin. Invest., 91:2463-2469 (1993);Reddy, S., et al., Biochem., 34:10872-10878 (1995); Dyer, D., et al., J.BioL Chem., 266:11654-11660 (1991); Degenhardt, T., et al., Cell Mol.Biol., 44:1139-1145 (1998)). Accumulation of AGEs in the vasculature canoccur focally, as in the joint amyloid composed of AGE-B₂-microglobulinfound in patients with dialysis-related amyloidosis (Miyata, T., et al.,J. Clin. Invest., 92:1243-1252 (1993); Miyata, T., et al., J. Clin.Invest., 98:1088-1094 (1996)), or generally, as exemplified by thevasculature and tissues of patients with diabetes (Schmidt, A-M., etal., Nature Med., 1:1002-1004 (1995)). The progressive accumulation ofAGEs over time in patients with diabetes suggests that endogenousclearance mechanisms are not able to function effectively at sites ofAGE deposition. Such accumulated AGEs have the capacity to altercellular properties by a number of mechanisms. Although RAGE isexpressed at low levels in normal tissues and vasculature, in anenvironment where the receptor's ligands accumulate, it has been shownthat RAGE becomes upregulated (Li, J. et al., J. Biol. Chem.,272:16498-16506 (1997); Li, J., et al., J. Biol. Chem., 273:30870-30878(1998); Tanaka, N., et al., J. Biol. Chem,. 275:25781-25790(2000)). RAGEexpression is increased in endothelium, smooth muscle cells andinfiltrating mononuclear phagocytes in diabetic vasculature. Also,studies in cell culture have demonstrated that AGE-RAGE interactioncaused changes in cellular properties important in vascular homeostasis.

II. RAGE and Cellular Dysfunction in the Amyloidoses

[0313] Also as noted above, the compounds of the present invention areuseful in treating amyloidoses and Alzheimer's disease. RAGE appears tobe a cell surface receptor which binds β-sheet fibrillar materialregardless of the composition of the subunits (amyloid-β peptide, Aβ,amylin, serum amyloid A, prion-derived peptide) (Yan, S. -D., et al.,Nature, 382:685-691 (1996); Yan, S-D., et al., Nat. Med., 6:643-651(2000)). Deposition of amyloid has been shown to result in enhancedexpression of RAGE. For example, in the brains of patients withAlzheimer's disease (AD), RAGE expression increases in neurons and glia(Yan, S. -D., et al., Nature 382:685-691 (1996)). The consequences of ABinteraction with RAGE appear to be quite different on neurons versusmicroglia. Whereas microglia become activated as a consequence ofAβ-RAGE interaction, as reflected by increased motility and expressionof cytokines, early RAGE-mediated neuronal activation is superceded bycytotoxicity at later times. Further evidence of a role for RAGE incellular interactions of AB concerns inhibition of AB-induced cerebralvasoconstriction and transfer of the peptide across the blood-brainbarrier to brain parenchyma when the receptor was blocked (Kumar, S., etal., Neurosci. Program, p141-#275.19 (2000)). Inhibition of RAGE-amyloidinteraction has been shown to decrease expression of cellular RAGE andcell stress markers (as well as NF-KB activation), and diminish amyloiddeposition (Yan, S-D., et al., .Nat. Med., 6:643-651 (2000)) suggestinga role for RAGE-amyloid interaction in both perturbation of cellularproperties in an environment enriched for amyloid (even at early stages)as well as in amyloid accumulation.

III. RAGE and Propagation of the Immune/Inflammatory Response

[0314] As noted above, the compounds of the present invention are usefulin treating inflammation. For example, S100/calgranulins have been shownto comprise a family of closely related calcium-binding polypeptidescharacterized by two EF-hand regions linked by a connecting peptide(Schafer, B. et al., TIBS, 21:134-140 (1996); Zimmer, D., et al., BrainRes. Bull., 37:417-429 (1995); Rammes, A., et al., J. Biol. Chem.,272:9496-9502 (1997); Lugering, N., et al., Eur. J Clin. Invest.,25:659-664 (1995)). Although they lack signal peptides, it has long beenknown that S100/calgranulins gain access to the extracellular space,especially at sites of chronic immune/inflammatory responses, as incystic fibrosis and rheumatoid arthritis. RAGE is a receptor for manymembers of the S100/calgranulin family, mediating their proinflammatoryeffects on cells such as lymphocytes and mononuclear phagocytes. Also,studies on delayed-type hypersensitivity response, colitis in IL-10 nullmice, collagen-induced arthritis, and experimental autoimmuneencephalitis models suggest that RAGE-ligand interaction (presumablywith S100/calgranulins) has a proximal role in the inflammatory cascade.

IV. RAGE and Amphoterin

[0315] As noted above, the compounds of the present invention are usefulin treating tumor and tumor metastasis. For example, amphoterin is ahigh mobility group I nonhistone chromosomal DNA binding protein(Rauvala, H., et al., J. Biol. Chem., 262:16625-16635 (1987);Parkikinen, J., et al., J. Biol. Chem. 268:19726-19738 (1993)) which hasbeen shown to interact with RAGE. It has been shown that amphoterinpromotes neurite outgrowth, as well as serving as a surface for assemblyof protease complexes in the fibrinolytic system (also known tocontribute to cell mobility). In addition, a local tumor growthinhibitory effect of blocking RAGE has been observed in a primary tumormodel (C6 glioma), the Lewis lung metastasis model (Taguchi, A., et al.,Nature 405:354-360 (2000)), and spontaneously arising papillomas in miceexpressing the v-Ha-ras transgene (Leder, A., et al., Proc. Natl. Acad.Sci., 87:9178-9182 (1990)).

[0316] Amphoterin is a high mobility group I nonhistone chromosomal DNAbinding protein (Rauvala, H. and R. Pihlaskari. 1987. Isolation and somecharacteristics of an adhesive factor of brain that enhances neuriteoutgrowth in central neurons. J. Biol. Chem. 262:16625-16635.(Parkikinen, J., E. Raulo, J. Merenmies, R. Nolo, E. Kajander, M.Baumann, and H. Rauvala. 1993. Amphoterin, the 30 kDa protein in afamily of HIMG1-type polypeptides. J. Biol. Chem. 268:19 726-19738).

V. RAGE and Erectile Dysfunction

[0317] Relaxation of the smooth muscle cells in the cavemosal arteriolesand sinuses results in increased blood flow into the penis, raisingcorpus cavemosum pressure to culminate in penile erection. Nitric oxideis considered the principle stimulator of cavemosal smooth musclerelaxation (See Wingard C J, Clinton W, Branam H, Stopper V S, Lewis RW, Mills T M, Chitaley K. Antagonism of Rho-kinase stimulates rat penileerection via a nitric oxide-independent pathway. Nature Medicine January2001;7(1):119-122). RAGE activation produces oxidants (See Yan, S-D.,Schmidt A-M., Anderson, G., Zhang, J., Brett, J., Zou, Y-S., Pinsky, D.,and Stern, D. Enhanced cellular oxidant stress by the interaction ofadvanced glycation endproducts with their receptors/binding proteins. J.Biol. Chem. 269:9889-9887, 1994.) via an NADH oxidase-like enzyme,therefore suppressing the circulation of nitric oxide. Potentially byinhibiting the activation of RAGE signaling pathways by decreasing theintracellular production of AGEs, generation of oxidants will beattenuated. RAGE blockers may promote and facilitate penile erection byblocking the access of ligands to RAGE.

[0318] The calcium-sensitizing Rho-kinase pathway may play a synergisticrole in cavernosal vasoconstriction to maintain penile flaccidity. Theantagonism of Rho-kinase results in increased corpus cavemosum pressure,initiating the erectile response independently of nitric oxide (Wingardet al.). One of the signaling mechanisms activated by RAGE involves theRho-kinase family such as cdc42 and rac (See Huttunen H J, Fages C,Rauvala H. Receptor for advanced glycation end products (RAGE)-mediatedneurite outgrowth and activation of NF-kappaB require the cytoplasmicdomain of the receptor but different downstream signaling pathways. JBiol Chem Jul. 9, 1999;274(28):19919-24). Thus, inhibiting activation ofRho-kinases via suppression of RAGE signaling pathways will enhance andstimulate penile erection independently of nitric oxide.

[0319] Thus, in a further aspect, the present invention provides amethod for the inhibition of the interaction of RAGE with physiologicalligands. In a preferred embodiment of this aspect, the present inventionprovides a method for treating a disease state selected from the groupconsisting of acute and chronic inflammation, symptoms of diabetes,vascular permeability, nephropathy, atherosclerosis, retinopathy,Alzheimer's disease, erectile dysfunction, and tumor invasion and/ormetastasis, which comprises administering to a subject in need thereof acompound of the present invention, preferably a pharmacologicallyeffective amount, more preferably a therapeutically effective amount. Ina preferred embodiment, at least one compound of Formula (I) isutilized, either alone or in combination with one or more knowntherapeutic agents. In a further preferred embodiment, the presentinvention provides method of prevention and/or treatment of RAGEmediated human diseases, treatment comprising alleviation of one or moresymptoms resulting from that disorder, to an outright cure for thatparticular disorder or prevention of the onset of the disorder, themethod comprising administration to a human in need thereof atherapeutically effective amount of a compound of the present invention,preferably a compound of Formula (I).

[0320] In this method, factors which will influence what constitutes aneffective amount will depend upon the size and weight of the subject,the biodegradability of the therapeutic agent, the activity of thetherapeutic agent, as well as its bioavailability. As used herein, thephrase “a subject in need thereof” includes mammalian subjects,preferably humans, who either suffer from one or more of the aforesaiddiseases or disease states or are at risk for such. Accordingly, in thecontext of the therapeutic method of the invention, this method also iscomprised of a method for treating a mammalian subject prophylactically,or prior to the onset of diagnosis such disease(s) or disease state(s).

[0321] In a further aspect of the present invention, the RAGE modulatorsof the invention are utilized in adjuvant therapeutic or combinationtherapeutic treatments with other known therapeutic agents.

[0322] The term “treatment” as used herein, refers to the full spectrumof treatments for a given disorder from which the patient is suffering,including alleviation of one, most of all symptoms resulting from thatdisorder, to an outright cure for the particular disorder or preventionof the onset of the disorder.

[0323] The following is a non-exhaustive listing of adjuvants andadditional therapeutic agents which may be utilized in combination withthe RAGE modulators of the present invention:

[0324] Pharmacologic classifications of anticancer agents:

[0325] 1. Alkylating agents: Cyclophosphamide, nitrosoureas,carboplatin, cisplatin, procarbazine

[0326] 2. Antibiotics: Bleomycin, Daunorubicin, Doxorubicin

[0327] 3. Antimetabolites: Methotrexate, Cytarabine, Fluorouracil

[0328] 4. Plant alkaloids: Vinblastine, Vincristine, Etoposide,Paclitaxel,

[0329] 5. Hormones: Tamoxifen, Octreotide acetate, Finasteride,Flutamide

[0330] 6. Biologic response modifiers: Interferons, Interleukins,

[0331] Pharmacologic classifications of treatment for RheumatoidArthritis (Inflammation)

[0332] 1. Analgesics: Aspirin

[0333] 2. NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen,Naproxen, Diclofenac

[0334] 3. DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate,gold preparations, hydroxychloroquine, sulfasalazine

[0335] 4. Biologic Response Modifiers, DMARDs: Etanercept, InfliximabGlucocorticoids

[0336] Pharmacologic classifications of treatment for Diabetes Mellitus

[0337] 1. Sulfonylureas: Tolbutamide, Tolazamide, Glyburide, Glipizide

[0338] 2. Biguanides: Metformin

[0339] 3. Miscellaneous oral agents: Acarbose, Troglitazone

[0340] 4. Insulin

[0341] Pharmacologic classifications of treatment for Alzheimer'sDisease

[0342] 1. Cholinesterase Inhibitor: Tacrine, Donepezil

[0343] 2. Antipsychotics: Haloperidol, Thioridazine

[0344] 3. Antidepressants: Desipramine, Fluoxetine, Trazodone,Paroxetine

[0345] 4. Anticonvulsants: Carbamazepine, Valproic acid

[0346] In a further preferred embodiment, the present invention providesa method of treating RAGE mediated diseases, the method comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of Formula (I) in combination with therapeuticagents selected from the group consisting of alkylating agents,antimetabolites, plant alkaloids, antibiotics, hormones, biologicresponse modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids,sulfonylureas, biguanides, insulin, cholinesterase inhibitors,antipsychotics, antidepressants, and anticonvulsants. In a furtherpreferred embodiment, the present invention provides the pharmaceuticalcomposition of the invention as described above, further comprising oneor more therapeutic agents selected from the group consisting ofalkylating agents, antimetabolites, plant alkaloids, antibiotics,hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs,glucocorticoids, sulfonylureas, biguanides, insulin, cholinesteraseinhibitors, antipsychotics, antidepressants, and anticonvulsants.

[0347] Generally speaking, the compound of the present invention,preferably Formula (I), is administered at a dosage level of from about0.01 to 500 mg/kg of the body weight of the subject being treated, witha preferred dosage range between 0.01 and 200 mg/kg, most preferably 0.1to 100 mg/kg of body weight per day. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage will vary depending upon the host treated and the particular modeof administration. For example, a formulation intended for oraladministration to humans may contain 1 mg to 2 grams of a compound ofFormula (I) with an appropriate and convenient amount of carriermaterial which may vary from about 5 to 95 percent of the totalcomposition. Dosage unit forms will generally contain between from about5 mg to about 500 mg of active ingredient. This dosage has to beindividualized by the clinician based on the specific clinical conditionof the subject being treated. Thus, it will be understood that thespecific dosage level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, rate of excretion, drugcombination and the severity of the particular disease undergoingtherapy.

[0348] While the invention has been described and illustrated withreference to certain preferred embodiments therof, those skilled in theart will appreciate that various changes, modifications andsubstitutions can be made therein without departing from the spirit andscope of the invention. For example, effective dosages other than thepreferred dosages as set forth herein may be applicable as a consequenceof variations in the responsiveness of the mammal being treated forRAGE-mediated disease(s). Likewise, the specific pharmacologicalresponses observed may vary according to and depending on the particularactive compound selected or whether there are present pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention.

We claim:
 1. A compound comprising at least one moiety of the formula

wherein L₁ and L₂ are each a hydrocarbon group of from 1 to 6 carbons ora direct bond, and Aryl₁ and Aryl₂ are aryl, wherein each of Aryl₁ andAryl₂ are substituted by at least one lipophilic group.
 2. The compoundof claim 1, wherein the lipophilic group is selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylaryl, or C₁-C₆ alkoxyaryl.
 3. A compound ofFormula (I):

wherein R₁ and R₂ are independently selected from a) —H; b) —C₁₋₆ alkyl;c) -aryl; d) —C₁₋₆ alkylaryl; e) —C(O)—O—C₁₋₆ alkyl; f) —C(O)—O—C₁₋₆alkylaryl; g) —C(O)—NH—C₁₋₆ alkyl; h) —C(O)—NH—C₁₋₆ alkylaryl; i)—SO₂—C₁₋₆ alkyl; j) —SO₂—C₁₋₆ alkylaryl; k) —SO₂-aryl; l) —SO₂—NH—C₁₋₆alkyl; m) —SO₂—NH—C₁₋₆ alkylaryl; n)

o) —C(O)—C₁₋₆ alkyl; and p) —C(O)—C₁₋₆ alkylaryl; R₃ is selected from a)—C₁₋₆ alkyl; b) -aryl; and c) —C₁₋₆ alkylaryl; R₄ is selected from a)—C₁₋₆ alkylaryl; b) —C₁₋₆ alkoxyaryl; and c) -aryl; R₅ and R₆ areindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆ alkylaryl, and aryl; and wherein the aryl and/or alkylgroup(s) in R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₈, R₁₉, and R₂₀may be optionally substituted 1-4 times with a substituent group,wherein said substituent group(s) or the term substituted refers togroups selected from the group consisting of: a) —H; b) —Y—C₁₋₆ alkyl;—Y-aryl; —Y—C—₁₋₆ alkylaryl; —Y—C₁₋₆-alkyl-NR₇R₈; and—Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are, independently selected fromthe group consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—,—NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

and c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and R₁₈ and R₁₉are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂ _(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, and/or R₅ and R₆ may, independently, be takentogether to form a ring having the formula —(CH₂)_(m)—X—(CH₂ _(n)—bonded to the nitrogen atoms to which R₅ and R₆ are attached, wherein mand n are, independently, 1, 2, 3, or 4; X is selected from the groupconsisting of —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—,—NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

or a pharmaceutically acceptable salt, solvate or prodrug thereof. 4.The compound of claim 3, wherein: R₁ is hydrogen; R₂ is selected from a)—H; b) —C₁₋₆ alkyl; c) —C₁₋₆ alkylaryl; d) —C(O)—O—C₁₋₆ alkyl; e)—C(O)—NH—C₁₋₆ alkyl; f) —C(O)—NH—C₁₋₆ alkylaryl; g) —SO₂—C₁₋₆ alkyl; h)—SO₂—C₁₋₆ alkylaryl; i) —SO₂—NH—C₁₋₆ alkyl; and j)

k) —C(O)—C₁₋₆ alkyl; l) —C(O)—C₁₋₆ alkylaryl; R₃ is selected from a)—C₁₋₄ alkylaryl; and R₄ is selected from a) —C₁₋₆ alkylaryl; and b)-aryl; and wherein the aryl group in R₁, R₂, R₃ and R₄ is optionallysubstituted 1-4 times with a substituent group, wherein said substituentgroup(s) or the term substituted refers to groups selected from thegroup consisting of: a) —H; b) —Y—C₁₋₆ alkyl; —Y-aryl; —Y—C—₁₋₆alkylaryl; —Y—C₁₋₆-alkyl-NR₇R₈; and —Y—C₁₋₆-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

and c) halogen, hydroxyl, carbamoyl, and carboxyl; R₁₈ and R₁₉ areselected from the group consisting of aryl, C₁-C₆ alkyl, C₁-C₆alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ is selected from thegroup consisting of aryl, C₁-C₆ alkyl, or C₁-C₆ alkylaryl, and whereinR₇ and R₈ are selected from the group consisting of hydrogen, aryl,C₁-C₆ alkyl, or C₁-C₆ alkylaryl; and wherein R₇ and R₈ may be takentogether to form a ring having the formula —(CH₂)_(m)—X—(CH₂ _(n)—bonded to the nitrogen atom to which R₇ and R₈ are attached, and/or R₅and R₆ may, independently, be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂ _(n)— bonded to the nitrogen atoms to which R₅and R₆ are attached, wherein m, n, and X are as defined in claim
 3. 5.The compound of claim 3, wherein R₃ is C₁₋₃ alkylaryl and R₄ is aryl. 6.The compound of claim 5, wherein the aryl is substituted with —Y—C—₁₋₆alkylaryl.
 7. The compound of claim 3, wherein R₂ is —C(O)—O—C₁₋₆ alkyl.8. The compound of claim 3, wherein R₃ is C₁₋₃ alkylaryl, said aryloptionally substituted by substituted 1-4 times with a substituentgroup, wherein said substituent group(s) or the term substituted refersto groups selected from the group consisting of: —Y—C₁₋₆ alkyl; —Y-aryl;—Y—C—₁₋₆ alkylaryl; —Y—C₁₋₆-alkyl-NR₇R₈; and —Y—C₁₋₆-alkyl-W—R₂₀;wherein Y and W are, independently selected from the group consisting of—CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,—SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,


9. The compound of claim 8, wherein aryl is phenyl or napthyl,optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaryl, orC₁₋₆ alkoxyaryl.
 10. The compound of claim 3, wherein said compound isselected from the group consisting of compounds of the followingformulae:

or the free amine, free acid, solvate, prodrug, or pharmaceuticallyacceptable salt thereof.
 11. A pharmaceutical composition comprising acompound of claim 1 together with one or more pharmaceuticallyacceptable carriers or diluents.
 12. The pharmaceutical composition ofto claim 11, in the form of an oral dosage or parenteral dosage unit.13. The pharmaceutical composition of claim 11, wherein said compound isadministered as a dose in a range from about 0.01 to 500 mg/kg of bodyweight per day.
 14. The pharmaceutical composition of claim 11, whereinsaid compound is administered as a dose in a range from about 0.01 to200 mg/kg of body weight per day.
 15. The pharmaceutical composition ofclaim 11, wherein said compound is administered as a dose in a rangefrom about 0.1 to 100 mg/kg of body weight per day.
 16. A pharmaceuticalcomposition comprising compound of Formula (I):

wherein R₁ and R₂ are independently selected from a) —H; b) —C₁₋₆ alkyl;c) -aryl; d) —C₁₋₆ alkylaryl; e) —C(O)—O—C₁₋₆ alkyl; f) —C(O)—O—C₁₋₆alkylaryl; g) —C(O)—NH—C₁₋₆ alkyl; h) —C(O)—NH—C₁₋₆ alkylaryl; i)—SO₂—C₁₋₆ alkyl; j) —SO₂—C₁₋₆ alkylaryl; k) —SO₂-aryl; l) —SO₂—NH—C₁₋₆alkyl; m) —SO₂—NH—C₁₋₆ alkylaryl; n)

o) —C(O)—C₁₋₆ alkyl; and p) —C(O)—C₁₋₆ alkylaryl; R₃ is selected from a)—C₁₋₆ alkyl; b) -aryl; and c) —C₁₋₆ alkylaryl; R₄ is selected from a)—C₁₋₆ alkylaryl; b) —C₁₋₆ alkoxyaryl; and c) -aryl; R₅ and R₆ areindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆ alkylaryl, and aryl; and wherein the aryl and/or alkylgroup(s) in R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₈, R₁₉, and R₂₀may be optionally substituted 1-4 times with a substituent group,wherein said substituent group(s) or the term substituted refers togroups selected from the group consisting of: a) —H; b) —Y—C₁₋₆ alkyl;—Y-aryl; —Y—C—₁₋₆ alkylaryl; —Y—C₁₋₆-alkyl-NR₇R₈; and—Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are, independently selected fromthe group consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—,—NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and R₁₈ and R₁₉ areindependently selected from the group consisting of aryl, C₁-C₆ alkyl,C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ is selectedfrom the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; R₇,R₈, R₉ and R₁₀ are independently selected from the group consisting ofhydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; and wherein R₇ and R₈may be taken together to form a ring having the formula—(CH₂)_(m)—X—(CH₂ _(n)— bonded to the nitrogen atom to which R₇ and R₈are attached, and/or R₅ and R₆ may, independently, be taken together toform a ring having the formula —(CH₂)_(m)—X—(CH₂ _(n)— bonded to thenitrogen atoms to which R₅ and R₆ are attached, wherein m and n are,independently, 1, 2, 3, or 4; X is selected from the group consisting of—CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,—NHSO₂—, —SO₂N(H)—,

or a pharmaceutically acceptable salt, solvate or prodrug thereof; andone or more pharmaceutically acceptable carriers, excipients, ordiluents.
 17. The composition of claim 16, wherein: R₁ is hydrogen; R₂is selected from a) —H; b) —C₁₋₆ alkyl; c) —C₁₋₆ alkylaryl; d)—C(O)—O—C₁₋₆ alkyl; e) —C(O)—NH—C₁₋₆ alkyl; f) —C(O)—NH—C₁₋₆ alkylaryl;g) —SO₂—C₁₋₆ alkyl; h) —SO₂—C₁₋₆ alkylaryl; i) —SO₂—NH—C₁₋₆ alkyl; andj)

k) —C(O)—C₁₋₆ alkyl; l) —C(O)—C₁₋₆ alkylaryl; R₃ is selected from a)—C₁₋₄ alkylaryl; and R₄ is selected from a) —C₁₋₆ alkylaryl; and b)-aryl; and wherein the aryl group in R₁, R₂, R₃ and is optionallysubstituted 1-4 times with a substituent group, wherein said substituentgroup(s) or the term substituted refers to groups selected from thegroup consisting of: a) —H; b) —Y—C₁₋₆ alkyl; —Y-aryl; —Y—C—₁₋₆alkylaryl; —Y—C₁₋₆-alkyl-NR₇R₈; and —Y—C₁₋₆-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

and c) halogen, hydroxyl, carbamoyl, and carboxyl; R₁₈ and R₁₉ areselected from the group consisting of aryl, C₁-C₆ alkyl, C₁-C₆alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ is selected from thegroup consisting of aryl, C₁-C₆ alkyl, or C₁-C₆ alkylaryl, and whereinR₇ and R₈ are selected from the group consisting of hydrogen, aryl,C₁-C₆ alkyl, or C₁-C₆ alkylaryl; and wherein R₇ and R₈ may be takentogether to form a ring having the formula —(CH₂)_(m)—X—(CH₂ _(n)—bonded to the nitrogen atom to which R₇ and R₈ are attached, and/or R₅and R₆ may, independently, be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂ _(n)— bonded to the nitrogen atoms to which R₅and R₆ are attached, wherein m, n, and X are as defined in claim
 16. 18.The composition of claim 16, wherein R₃ is C₁₋₃ alkylaryl and R₄ isaryl.
 19. The composition of claim 18, wherein the aryl is substitutedwith —Y—C—₁₋₆ alkylaryl.
 20. The composition of claim 16, wherein R₂ is—C(O)—O—C₁₋₆ alkyl.
 21. The composition of claim 16, wherein R₃ is C₁₋₃alkylaryl, said aryl optionally substituted by substituted 1-4 timeswith a substituent group, wherein said substituent group(s) or the termsubstituted refers to groups selected from the group consisting of:—Y—C₁₋₆ alkyl; —Y-aryl; —Y—C—₁₋₆ alkylaryl; —Y—C₁₋₆-alkyl-NR₇R₈; and—Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are, independently selected fromthe group consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—,—NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,


22. The composition of claim 21, wherein aryl is phenyl or napthyl,optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaryl, orC₁₋₆ alkoxyaryl.
 23. The composition of claim 16, wherein said compoundis selected from the group consisting of compounds of the formulae:

or the free amine, free acid, solvate, prodrug, or pharmaceuticallyacceptable salt thereof.
 24. The pharmaceutical composition of claim 16,in the form of an oral dosage or parenteral dosage unit.
 25. Thepharmaceutical composition of claim 16, wherein said compound isadministered as a dose in a range from about 0.01 to 500 mg/kg of bodyweight per day.
 26. The pharmaceutical composition of claim 16, whereinsaid compound is administered as a dose in a range from about 0.1 to 200mg/kg of body weight per day.
 27. The pharmaceutical composition ofclaim 16, wherein said compound is administered as a dose in a rangefrom about 0.1 to 100 mg/kg of body weight per day.
 28. Thepharmaceutical composition of claim 16, further comprising one or moretherapeutic agents selected from the group consisting of alkylatingagents, antimetabolites, plant alkaloids, antibiotics, hormones,biologic response modifiers, analgesics, NSAIDs, DMARDs,glucocorticoids, sulfonylureas, biguanides, insulin, cholinesteraseinhibitors, antipsychotics, antidepressants, and anticonvulsants.
 29. Amethod for the inhibition of the interaction of RAGE with itsphysiological ligands, which comprises administering to a subject inneed thereof, at least one compound comprising at least one moiety ofthe formula

wherein L₁ and L₂ are each a hydrocarbon group of from 1 to 6 carbons ora direct bond, and Aryl₁ and Aryl₂ are aryl, wherein each of Aryl₁ andAryl₂ are substituted by at least one lipophilic group.
 30. The methodof claim 29, wherein the ligand(s) is(are) selected from advancedglycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid andamphoterin.
 31. A method for the inhibition of the interaction of RAGEwith its physiological ligands, which comprises administering to asubject in need thereof, at least one compound of Formula (I) as claimedin claim
 3. 32. A method for treating a disease state selected from thegroup consisting of acute and chronic inflammation, symptoms ofdiabetes, vascular permeability, nephropathy, atherosclerosis,retinopathy, Alzheimer's disease, erectile dysfunction, and tumorinvasion and/or metastasis, which comprises administering to a subjectin need thereof a therapeutically effective amount of at least onecompound comprising at least one moiety of the formula

wherein L₁ and L₂ are each a hydrocarbon group of from 1 to 6 carbons,or a direct bond, and Aryl₁ and Aryl₂ are aryl, wherein each of Aryl₁and Aryl₂ are substituted by at least one lipophilic group.
 33. Themethod of claim 32, further comprising administering to a subject inneed thereof at least one adjuvant and/or additional therapeuticagent(s).
 34. A method of prevention and/or treatment of RAGE mediatedhuman diseases, treatment comprising alleviation of one or more symptomsresulting from that disorder, to an outright cure for that particulardisorder or prevention of the onset of the disorder, the methodcomprising administration to a human in need thereof a therapeuticallyeffective amount of a compound of Formula (I) as claimed in claim
 3. 35.A method for treating acute and/or chronic inflammation, which comprisesadministering to a subject in need thereof a therapeutically effectiveamount of a compound of Formula (I) as claimed in claim
 3. 36. A methodfor treating vascular permeability, which comprises administering to asubject in need thereof a therapeutically effective amount of a compoundof Formula (I) as claimed in claim
 3. 37. A method for treatingnephropathy, which comprises administering to a subject in need thereofa therapeutically effective amount of a compound of Formula (I) asclaimed in claim
 3. 38. A method for treating atherosclerosis, whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula (I) as claimed in claim
 3. 39.A method for treating retinopathy, which comprises administering to asubject in need thereof a therapeutically effective amount of compoundof Formula (I) as claimed in claim
 3. 40. A method for treatingAlzheimer's disease, which comprises administering to a subject in needthereof a therapeutically effective amount of a compound of Formula (I)as claimed in claim
 3. 41. A method for treating erectile dysfunction,which comprises administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I) as claimedin claim
 3. 42. A method for treating tumor invasion and/or metastasis,which comprises administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I) as claimedin claim
 3. 43. A method of treating RAGE mediated diseases, the methodcomprising administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of Formula (I) as claimed in claim 3, incombination with one or more therapeutic agents selected from the groupconsisting of alkylating agents, antimetabolites, plant alkaloids,antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs,DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin,cholinesterase inhibitors, antipsychotics, antidepressants, andanticonvulsants.
 44. A process for preparing a compound of the Formula(II)

which comprises the steps: (a) reacting a compound of the formula

with an amine of the formula R₄—NH₂, in the presence of a couplingreagent to form a compound of the formula

followed by removal of the protecting group PG, wherein R₃ is selectedfrom a) —C₁₋₆ alkyl; b) -aryl; and c) —C₁₋₆ alkylaryl; R₄ is selectedfrom a) —C₁₋₆ alkylaryl; b) —C₁₋₆ alkoxyaryl; and c) -aryl; and whereinthe aryl and/or alkyl group(s) in R₃ and R₄ may be optionallysubstituted 1-4 times with a substituent group, wherein said substituentgroup(s) or the term substituted refers to groups selected from thegroup consisting of: a) —H; b) —Y—C₁₋₆ alkyl; —Y-aryl; —Y—C—₁₋₆alkylaryl; —Y—C₁₋₆-alkyl-NR₇R₈; and —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and Ware, independently selected from the group consisting of —CH₂—, —O—,—N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—,—C(O)—O—, —NHSO₂NH—, —O—CO—,

and c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and R₁₈ and R₁₉are selected from the group consisting of aryl, C₁-C₆ alkyl, C₁-C₆alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ is selected from thegroup consisting of aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; R₇ and R₈are selected from the group consisting of hydrogen, aryl, C₁-C₆ alkyl,and C₁-C₆ alkylaryl; and wherein R₇ and R₈ may be taken together to forma ring having the formula —(CH₂)_(m)—X—(CH₂ _(n)— bonded to the nitrogenatom to which R₇ and R₈ are attached, wherein m and n are,independently, 1, 2, 3, or 4; X is —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—,—CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—,—NHSO₂NH—,

and PG is an amino protecting group.
 45. A process for preparing acompound of Formula (III)

which comprises reacting a compound of Formula (II)

(A) with an aldehyde or ketone of the formula R₁₂C(O)R₁₁ in the presenceof a reducing agent, wherein R₁₂ and R₁₁ are independently selected froma) —H; b) —C₁₋₆ alkyl; c) -aryl; d) —C₁₋₆ alkylaryl; e) —C(O)—O—C₁₋₆alkyl; f) —C(O)—O—C₁₋₆ alkylaryl; g) —C(O)—NH—C₁₋₆ alkyl; h)—C(O)—NH—C₁₋₆ alkylaryl; i) —SO₂—C₁₋₆ alkyl; j) —SO₂—C₁₋₆ alkylaryl; k)—SO₂-aryl; l) —SO₂—NH—C₁₋₆ alkyl; m) —SO₂—NH—C₁₋₆ alkylaryl; n)

o) —C(O)—C₁₋₆ alkyl; and p) —C(O)—C₁₋₆ alkylaryl; and wherein the aryland/or alkyl group(s) in R₁ and R₂ may be optionally substituted 1-4times with a substituent group, wherein said substituent group(s) or theterm substituted refers to groups selected from the group consisting of:a) —H; b) —Y—C₁₋₆ alkyl; —Y-aryl; —Y—C—₁₋₆ alkylaryl;—Y—C₁₋₆-alkyl-NR₇R₈; and —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

and c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and R₇ and R₈are selected from the group consisting of hydrogen, aryl, C₁-C₆ alkyl,and C₁-C₆ alkylaryl; R₁₈ and R₁₉ are selected from the group consistingof aryl, C₁-C₆ alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆alkoxyaryl; R₂₀ is selected from the group consisting of aryl, C₁-C₆alkyl, and C₁-C₆ alkylaryl; and wherein R₇ and R₈ may be taken togetherto form a ring having the formula —(CH₂)_(m)—X—(CH₂ _(n)— bonded to thenitrogen atom to which R₇ and R₈ are attached, and/or R₅ and R₆ may,independently, be taken together to form a ring having the formula—(CH₂)_(m)—X—(CH₂ _(n)— bonded to the nitrogen atoms to which R₅ and R₆are attached, wherein m and n are, independently, 1, 2, 3, or 4; X is—CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,—NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

or (B) with a tertiary amine base and an alkylating agent of the formulaR₂—Z, wherein Z is a nucleofugal group, and R₂ is as defined above forR₁₂ or R₁₁.
 46. A process for preparing a compound of Formula (IV)

which comprises either (a) treating a compound of the formula

with a compound of the formula R₁₄SO₂Cl, wherein R₁₄ is C₁₋₆ alkyl, C₁₋₆alkylaryl, or aryl, or (b) treating an amine compound of the formulaR₁₋₅—NH₂ with sulfuryl chloride, to afford an intermediate which is thencontacted with a compound of the formula

wherein R₃, R₄, and PG are as defined in claim
 44. 47. A process forpreparing a compound of Formula (V)

which comprises contacting a compound of Formula (II)

wherein R₃ and R₄ are as defined in claim 44, with a compound of theformula R₁₅NCO, optionally in the presence of a tertiary amine, whereinR₁₅ is —C₁₋₆ alkyl or —C₁₋₆ alkylaryl and Q is —NH—.
 48. A process forpreparing a compound of Formula (V)

which comprises contacting a compound of Formula (II)

as defined in claim 47, with a compound of the formula R₁₅O—C(O)Cl and atertiary amine base, wherein R₁₄ is —C₁₋₆ alkyl or —C₁₋₆ alkylaryl and Qis −O—.
 49. A process for preparing a compound of Formula (VI)

which comprises contacting a compound of the formula

with triphenylphosphine and either (a) diisopropyl azodicarboxylate ordiethy azodicarboxylate and an alcohol of the formula R₁₆OH, followed bytreatment with a strong base or strong acid, depending upon the identityof PG; wherein PG is a urethane-type blocking group; and R₁₆ is C₁₋₆alkyl, —C₁₋₆ alkylaryl, —C₁₋₆ alkyl-Si(C₁₋₆ alkyl)₃, —C₁₋₆alkyl-OSi(C₁₋₆ alkylaryl)₃, or —C₁₋₆ alkyl-NR₇R₈, provided that neitherof R₇ and R₈ are hydrogen.
 50. A process for preparing a compound ofFormula (VII)

which comprises contacting a compound of the formula

with either (a) a compound of the formula (R₁₇—CO)₂O, in the presence ofa tertiary amine; (b) a compound of the formula R₁₇—C(O)Cl, in thepresence of a tertiary amine; or (c) a compound of the formulaR₁₇—C(O)OH and a coupling reagent. wherein R₁₇ is C₁₋₆ alkyl or C₁₋₆alkylaryl; and R₃ and R₄ are as defined in claim
 44. 51. A process forpreparing a compound of Formula (VIII)

wherein R₃ and R₄ are as defined in claim 43, and R₅ and R₆ areindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆ alkylaryl, and aryl; and/or R₅ and R₆ may, independently,be taken together to form a ring having the formula —(CH₂)_(m)—X—(CH₂_(n)— bonded to the nitrogen atoms to which R₅ and R₆ are attached,wherein m and n are, independently, 1, 2, 3, or 4; X is selected fromthe group consisting of —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—,—NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

which comprises contacting a compound of the formula

with an activated amidine reagent of the formula

in the presence of a tertiary amine, followed by treatment with a strongacid, wherein BOC represents tert-butoxycarbonyl-.